Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

Abstract

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)–associated ALI.

Effects of cold or warm ischemia and ex-vivo lung perfusion on the release of damage associated molecular patterns and inflammatory cytokines in experimental lung transplantation

“…A candidate might be mitochondrial DNA, which has been detected in the EVLP perfusate of rat lungs (35), and in the BAL and plasma following LTx (36,37). Another possibility is that inflammation arises during EVLP independently from DAMP release, for example through the activation of the enzyme poly(ADP-ribose) polymerase (PARP), as recently proposed by our group (5,38), or could simply reflect the presence of endogenous inflammatory cells in the graft (39).…”

Effects of the PARP Inhibitor Olaparib on the Response of Human Peripheral Blood Leukocytes to Bacterial Challenge or Oxidative Stress

“…Resistance to inflammation has been observed in PARP1 knockout mice subjected to various forms of injury including reperfusion and inflammation [ 1 , 2 ]. Also, PARP1 activation plays a significant role in the pathogenesis of ARDS [ 27 , 28 , 29 ]. Pediatric patients with serious burn injuries reportedly presented with PARP1 activation, as demonstrated by increased PARylation in endothelial cells and leukocytes from muscle tissue [ 24 ].…”

Advances in cGAS-STING Signaling Pathway and Diseases

“…The PARP inhibitors (e.g., Olaparib and talazoparib) are known to have promising therapeutic efficacy in BRCA-associated breast cancers (Robson et al, 2017;Litton et al, 2018). Besides, the beneficial pharmacological effects of PARP inhibitors were observed on inflammatory diseases, such as liver inflammation and fibrosis (Mukhopadhyay et al, 2014), asthma (Zaffini et al, 2018), and acute and chronic mice lung injury (Szabo et al, 2020). Recently, Pantelidou et al revealed that interaction of PARP inhibition and STING/TBK1/IRF3 pathway activation regulates T cell recruitment and anti-tumor efficacy in cancer cells (Pantelidou et al, 2019).…”